Project Summary Functional gastrointestinal (GI) disorders such as chronic constipation, functional dyspepsia and irritable bowel syndrome (IBS) are highly prevalent but have few definitive treatments. IBS alone affects more than 10% of the U.S. population, causing chronic abdominal pain and altered GI motility leading to debilitating diarrhea and/or constipation. Prominent sex differences have been noted in IBS; men and women often present with different symptoms and exhibit different responses to treatment. Identifying the underlying basis of these sex differences will lead to more effective and personalized treatments for IBS. The enteric nervous system (ENS), which consists of the intrinsic nerve circuits of the bowel, is essential for regulating GI motility. Cellular, molecular, or circuit-level sex differences in the ENS may underlie sex differences in IBS, but this has been not been well studied. We have evidence that dysfunction in glial cells, the non-neuronal cells of the ENS, leads to a sexually dimorphic effect on colonic motility, and that enteric glia express receptors for sex hormones. The research objectives of this project are thus to determine: (1) how ongoing exposure to gonadal sex hormones, such as testosterone and estrogen, regulates colonic motility, and (2) how glia interact with intrinsic sensory neurons in the ENS to regulate colonic motility in a sex-dependent manner. Over the course of this 5 year career development award, the principal investigator will build upon her previous clinical training in gastroenterology as well as her strong research background in neuroscience, to gain new skills in studying sex differences in the ENS and adapting novel technologies to measuring neuronal activity in the bowel. These skills will be applied to a series of in vivo and ex vivo experiments in mouse genetic models, which are designed to test the hypothesis that sexual dimorphism in neuron-glia interactions within the ENS underlies sex differences in GI motility and functional disease. Successful completion of this project will shed new light on cellular mechanisms of sex differences in GI motility, and provide the principal investigator with the training and experience she needs to launch her independent research program in enteric neurobiology.